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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we examine a cell death process induced by reactive oxygen species (ROS) in the haemoflagellate Trypanosoma brucei brucei. Ca2+ distribution in cellular compartments was measured with stable transformants expressing aequorin targeted to the cytosol, nucleus or mitochondrion. Within 1.5 h of ROS production, mitochondrial Ca2+ transport was impaired and the Ca2+ barrier between the nuclear envelope and cytosol was disrupted. Consequently the mitochondrion did not accumulate Ca2+ efficiently in response to an extracellular stimulus, and excess Ca2+ accumulated in the nucleus. The terminal transferase deoxytidyl uridine end labelling assay revealed that, 5 h after treatment with ROS, extensive fragmentation of nuclear DNA occurred in over 90% of the cells. Permeability changes in the plasma membrane did not occur until an additional 2 h had elapsed. The intracellular Ca2+ buffer, EGTA acetoxymethyl ester, prevented DNA fragmentation and prolonged the onset of changes in cell permeability. Despite some similarities to apoptosis, nuclease activation was not a consequence of caspase 3, caspase 1, calpain, serine protease, cysteine protease or proteasome activity. Moreover, trypanosomes expressing mouse Bcl-2 were not protected from ROS even though protection from mitochondrial dysfunction and ROS have been reported for mammalian cells. Overall, these results demonstrate that Ca2+ pathways can induce pathology in trypanosomes, although the specific proteins involved might be distinct from those in metazoans.
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PMID:Reactive oxygen species activate a Ca2+-dependent cell death pathway in the unicellular organism Trypanosoma brucei brucei. 1022 56

Cuphiin D1 (CD1), a new macrocyclic hydrolyzable tannin isolated from Cuphea hyssopifolia, has been shown to exert antitumor activity both in vitro and in vivo. In this study, we explored the mechanism of the CD1-induced antitumor effect on human promyelocytic leukemia (HL-60) cells. The results showed that CD1 induced cytotoxicity in HL-60 cells and the IC50 was 16 microM after 36 h treatment. HL-60 cells treated with CD1 for 36 h decreased the uptake of [3H]-labeled thymidine, uridine and leucine in a dose dependent manner. Electron micrographs demonstrated that HL-60 cells treated with 16 microM CD1 for 36 h exhibited chromatin condensation, indicating the apoptosis occurrence. Flow cytometric analysis demonstrated the presence of apoptotic cells with low DNA content, a decrease of cell population at G2/M phase, and a concomitant increase of cell population at G1 phase. CD1 also caused DNA fragmentation and inhibited Bcl-2 expression in the HL-60 cells. These results suggest that the inhibition of Bcl-2 expression in HL-60 cell might account for the mechanism of CD1-induced apoptosis.
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PMID:Cuphiin D1, the macrocyclic hydrolyzable tannin induced apoptosis in HL-60 cell line. 1073 11

The purpose of this study was to examine the correlations among enhancement of apoptosis, cell proliferation and expression of oncogenes in gastric carcinomas induced by preoperative oral administration of 5-fluorouracil (5-FU). The occurrence of spontaneous apoptotic cell death in 42 patients with gastric carcinoma was analyzed in the biopsy specimens preoperatively. p53 status was examined by polymerase chain reaction-single strand confirmation polymorphism and sequencing. Fourteen patients received oral administration of 5-FU at 300 mg/body/day for 7 days preoperatively. For detection of apoptotic cells, apoptotic incidences (AIs) were examined by the terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate biotin nick end labeling method, on gastric carcinoma lesions based on the endoscopic findings before administration in the biopsy and resected tissues. Expressions of p53, Bcl-2, Bax gene and proliferating cell nuclear antigen (PCNA) were also examined by immunohistochemical staining. On preoperative biopsy, p53 point mutation was observed in 14 of the 42 tumors. The immunohistochemical staining status and point mutation of p53 gene (positive or negative) were identical in 32 of the 42 tumors (76.2%). The average AIs of the biopsy specimens were 1.58+/-1.26% on p53-negative staining (n=19) and 1.14+/-1.02% on p53-positive staining (n=23), a significant association was not recognized between p53 expression and AI. In the preoperative administration group, the PCNA labeling index was significantly higher in the biopsy specimens than in the resected tissues (43. 6+/-12.8% vs. 35.3+/-8.8%, p<0.01). In addition, postoperatively, the rate of AI was significantly more accelerated in p53-negative staining (n=6) than in p53-positive staining (n=8) (0.89+/-0. 65%right curved arrow 4.18+/-3.26%, p<0.05 vs. 1.20+/-0.60%right curved arrow 2.60+/-2.60%, NS). There was no significant correlation between AI and Bcl-2 or Bax staining. Immunohistochemical analysis of p53 and PCNA stainings in biopsy specimens appears to be a well-characterized indicator of sensitivity of chemotherapy in gastric carcinomas.
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PMID:Apoptosis, cell proliferation and expression of oncogenes in gastric carcinomas induced by preoperative administration of 5-fluorouracil. 1094 24

Apoptosis of sinusoidal endothelial cells (SECs) is one of the initial events in the development of ischemia-reperfusion injury of the liver. Glycine has been shown to diminish ischemia-reperfusion injury in the liver and improve graft survival in the rat liver transplantation model. Here, we investigated the effect of glycine on apoptosis of primary cultured rat SECs induced by vascular endothelial growth factor (VEGF) deprivation. Isolated rat SECs were cultured in EBM-2 medium supplemented with 10% fetal bovine serum (FBS) and growth factors including 20 ng/mL VEGF for 3 days. SECs at 3 days of culture showed spindle-like shapes; however, cells started shrinking and detaching from dishes by VEGF deprivation. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated d-uridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining in these conditions. Control SECs contained only a few percent of TUNEL-positive cells; however, they started increasing 4 hours after VEGF deprivation, and the percentage of TUNEL-positive cells reached about 50% at 8 hours and almost 100% at 16 hours after VEGF deprivation. Interestingly, this increase in TUNEL-positive cells after VEGF deprivation was prevented significantly when glycine (1-10 mmol/L) was added to the medium, the levels being around 60% of VEGF deprivation without glycine. Furthermore, strychnine (1 micromol/L), a glycine receptor antagonist, inhibited this effect of glycine, suggesting the possible involvement of the glycine receptor/chloride channel in the mechanism. Moreover, Bcl-2 protein levels in SECs were decreased 8 hours after VEGF deprivation, which was prevented almost completely by glycine. It is concluded that glycine prevents apoptosis of primary cultured SECs under VEGF deprivation.
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PMID:Glycine prevents apoptosis of rat sinusoidal endothelial cells caused by deprivation of vascular endothelial growth factor. 1096 Apr 47

In the adult small intestine, the dynamic renewal of the epithelium is characterized by a sequence of cell production in the crypts, cell maturation and cell migration to the tip of villi, where apoptosis is undertaken. Little is known about enterocytic apoptosis during development. In man, intestinal architectural features and functions are acquired largely by mid-gestation (18-20 wks); the question whether the establishment of enterocytic apoptotic processes parallels or not the acquisition of other intestinal functional features remains open. In the present study, we approached this question by examining enterocytic apoptosis during development of the human jejunum (9-20 wks gestation), using the ISEL (in situ terminal uridine deoxynucleotidyl nick-end labelling) method. Between 9 and 17 wks, apoptotic enterocytes were not evidenced. However, beginning at the 18 wks stage, ISEL-positive enterocytes were regularly observed at the tip of villi. Since the Bcl-2 family of proteins constitutes a critical checkpoint in apoptosis, acting upstream of the apoptotic machinery, we investigated the expression of six Bcl-2 homologs (Bcl-2, Bcl-X(L), Mcl-1, Bax, Bak, Bad) and one non-homologous associated molecule (Bag-1). By immunofluorescence, we found that all homologs analyzed were expressed by enterocytes between 9 and 20 wks. However, Bcl-2 homologs underwent a gradual compartmentalization of epithelial expression along the maturing crypt-villus axis, to establish gradients of expression by 18-20 wks. Western blot analyses indicated that the expression levels of Bcl-2 homologs were modulated during morphogenesis of the crypt-villus axis, in parallel to their gradual compartmentalization of expression. Altogether, these data suggest that regulatory mechanisms of human enterocytic apoptosis become established by mid-gestation (18-20 wks) and coincide with the maturation of the crypt-villus axis of cell proliferation, differentiation and renewal.
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PMID:Early establishment of epithelial apoptosis in the developing human small intestine. 1121 57

We investigated the induction of apoptosis by cadmium in NIH 3T3 murine fibroblasts. Apoptosis was triggered effectively by 10 microM CdCl2 within 24 h, under which conditions cell viability was reduced by 50%. Cadmium-induced apoptosis was demonstrated by both morphological and biochemical analysis. We have shown that cadmium concentrations of 5-20 microM caused nuclear fragmentation. Moreover, internucleosomal DNA fragmentation was evoked by 10-25 microM CdCl2 within 24 h, as detected by the formation of ladder patterns in DNA electrophoresis. Since the induction of programmed cell death occurs together with modifications in the cell cycle, we examined the ability of cadmium to block cell divisions by using a 5-bromo2-deoxy-uridine incorporation assay. Our results indicate that about 40% of treated cells are blocked in G0-G1 phase when exposed to 10 microM cadmium for 27 h. Finally, we addressed the question of whether the effect of cadmium could be prevented by suppressing apoptosis. Over-expression of the anti-apoptotic protein Bcl-2 in NIH 3T3 cells protects against cadmium toxicity, thus suggesting a role for Bcl-2 in the regulation of cadmium-induced apoptosis.
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PMID:Cadmium-induced apoptosis in murine fibroblasts is suppressed by Bcl-2. 1157 Jun 88

L-Glutamine (Gln) is known to have protective effect on the small intestine under deleterious stressful condition. Although the mechanism by which Gln confers intestinal cellular protection remains unclear, its potential role may be mediated via signal transduction including stress response genes and anti-apoptotic genes. Herein, we examined a possible role of stress response genes in warm ischemically injured small intestines. We measured mRNA and protein expression of heme oxygenase (HO)-1, Bcl-2 and Bax at different time points after Gln administration. Warm ischemia model was made by clamping of the superior mesenteric artery for 60 min. After reperfusion, tissue samples were taken for end labeling of nuclear DNA fragments (TdT-mediated d-uridine triphosphate biotin nick end labeling; TUNEL) and hematoxylin-eosin staining. In Gln-treated group, the substantial expression of HO-1 mRNA peaked at 3 h and reduced thereafter, while HO-1 protein synthesis was noted within 3 h and reached plateau thereafter. NO-1-positive components were markedly detected in the villus epithelial cells and crypts. The ratios of Bcl-2/Bax mRNA expression after Gln administration peaked at 3 h and reduced thereafter until 24 h. Bcl-2 immunoreactive protein was enhanced in Gln group, whereas Bax was faintly detected. Following reperfusion, less TUNEL-positive staining of the top of the villi and more prompt recovery of denuded villus epithelial cells were noted in Gln group, compared with those in untreated and lactated Ringer-treated control groups. In conclusion, a concomitant expression of anti-oxidative HO-1 and anti-apoptotic Bcl-2 molecules induced by non-toxic amino acid, Gln, may alleviate or even prevent intestinal warm ischemia and reperfusion injury, attenuating programmed cell death and promoting its reepithelialization.
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PMID:[Impact of stress response genes induced by L-glutamine on warm ischemia and reperfusion injury in the rat small intestine]. 1196 53

Cyclooxygenase-2 (COX-2) and Bcl-2 have been implicated in upper gastrointestinal tract carcinomas, but the underlying mechanisms are not known. In the present study we assessed the correlation of COX-2 and Bcl-2 to known cell kinetics in the glandular stomach mucosa of 104 Wistar rats given combinations of Helicobacter pylori, MNNG ( N'-methyl- N'-nitro- N-nitrosoguanidine) and bile. COX-2 expression, Bcl-2 and cell proliferation (Ki-67) in antral and corpus mucosa were determined immunohistochemically. Apoptotic cells were detected using terminal uridine deoxynucleotidyl nick end labelling technique. Expression of COX-2 was found in the lower portion of glandular corpus epithelium, and Bcl-2 positivity was mainly seen in the proliferative zone of both antrum and corpus mucosa. COX-2 expression in histologically normal-appearing corpus mucosa was associated with cell proliferation, atrophy and intestinal metaplasia in antrum and with Bcl-2 expression in corpus mucosa. No correlation was found between apoptosis and Bcl-2 expression. MNNG but not H. pylori significantly increased COX-2 in corpus mucosa. H. pylori, however, promoted the COX-2 expression in corpus when bile was added and Bcl-2 expression in antrum. Abnormal expression of both COX-2 and Bcl-2 seem to be involved in H. pylori-induced gastric carcinogenesis by altering the gastric cell kinetics.
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PMID:Cyclooxygenase-2 and Bcl-2 expression in the stomach mucosa of Wistar rats exposed to Helicobacter pylori, N'-methyl- N'-nitro- N-nitrosoguanidine and bile. 1211 Dec 4

In the third trimester of normal pregnancy, the mother tolerates daily shedding of several grams of dying placental trophoblast into the maternal circulation. The balance between apoptotic and necrotic shedding is presently unknown. Since pre-eclampsia is characterized by an altered placental oxygenation and increased trophoblast shedding, we investigated the role of oxygen on the balance of apoptotic versus necrotic trophoblast shedding in vitro. We studied human trophoblast turnover in explanted villi from late first and third trimester placentas in low oxygen (2 per cent) and higher oxygen tensions (6 per cent and 18 per cent) for up to 72h. Trophoblast turnover including apoptosis and necrosis were assessed by histology, immunolocalization of Mib-1 (proliferation marker), Bcl-2 (apoptosis inhibitor), activated caspase 3 (apoptosis promoter), cytokeratin 18 neo-epitope formation (M30 antibody), TUNEL test (DNA degradation), and (3)H-cytidine and(3) H-uridine incorporations. Culture in 2 per cent oxygen increased cytotrophoblast proliferation and syncytiotrophoblast shedding by necrosis. The proteins necessary for execution of apoptosis were mostly retained in the cytotrophoblast due to lack of syncytial fusion. Culture in 6 per cent and 18 per cent oxygen reduced cytotrophoblast proliferation. Syncytial fusion occurred and activity of caspase 3 was found in the syncytiotrophoblast; the latter remained intact demonstrating physiologic turnover, including apoptotic shedding. We conclude that severe placental hypoxia favours necrotic rather than apoptotic shedding of syncytial fragments into the maternal circulation. Since uteroplacental ischaemia is a significant risk factor for pre-eclampsia, these findings may explain the link between reduced uteroplacental blood flow and the systemic clinical manifestations of this disease.
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PMID:Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation. 1256 45

We have shown previously that the decay of human bcl-2 mRNA is mediated by an adenine/uridine-rich element (ARE) located in the 3'-untranslated region. Here, we have utilized a non-radioactive cell-free mRNA decay system to investigate the biochemical and functional mechanisms regulating the ARE-dependent degradation of bcl-2 mRNA. Using RNA substrates, mutants, and competitors, we found that decay is specific and ARE-dependent, although maximized by the ARE-flanking regions. In unfractionated extracts from different cell types and in whole cells, the relative enzymatic activity was related to the amount of Bcl-2 protein expressed by the cells at steady state. The degradation activity was lost upon Bcl-2 depletion and was reconstituted by adding recombinant Bcl-2. Ineffective extracts from cells that constitutively do not express Bcl-2 acquire full degradation activity by adding recombinant Bcl-2 protein. We conclude that Bcl-2 is necessary to activate the degradation complex on the relevant RNA target.
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PMID:Bcl-2 protein is required for the adenine/uridine-rich element (ARE)-dependent degradation of its own messenger. 1270 30


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